Engineered nanomaterials have unique electrical, mechanical and physicochemical properties with potential to benefit our society. However, the health and safety of nanomaterials has recently become a great concern to the public, policymakers and regulatory agencies. Such concern is justified due to the vast potential use of nanomaterials in food, cosmetics, medicine, construction, manufacturing, and the environment. It has recently been established that nanomaterials, upon entry into the bloodstream or lung, exhibit a natural tendency of physical adsorption with proteins, peptides, lipids and amino acids to render a protein corona that may dictate the bioavailability and distribution of nanomaterials within the host system, at the cellular, tissue and organism level. Consequently, the objective of this application is to delineate the dynamic roles of nanoparticle-protein corona on biological responses to engineered nanomaterials for safe nanotechnologies and nanomedicines. Determining the health and safety implications of the nanoparticle-protein corona requires addressing the fundamental aspects of 1) dynamics and conformational changes resulting from competitive binding, crowding and degradation of the proteins, and 2) recognition of the protein corona by cellular receptors and immune responses. The central hypothesis of this project is that the physicochemical properties of the nanoparticle-protein corona entity are correlated with biological responses to the corona to impact on their uptake and hypersensitivity reactions. We will test this hypothesis by pursuing three specific aims: 1) Understand nanoparticle-protein interaction and transformation; 2) Determine the in silico structure and dynamics of protein corona; 3) Determine the in vitro impact of nanoparticle-protein corona on directing cellular uptake, ER stress and the unfolded protein response. The rationale of this application is that understanding the impact of nanoparticle-protein corona on cellular recognition, uptake and response is crucial for predicting toxicity and developing safe nanotechnologies. In addition, this R15 project is expected to contribute to the training of a new generation of scientists at the interface of biophysics and biomedicine and facilitate future NIH funding opportunities for Clemson University and East Carolina University.